DESCRIPTION (From the Applicant's Abstract): The long-term objectives of the proposed research are to elucidate the mechanisms that regulate cell death and survival in the developing mammalian central nervous system. The neurotrophin comprise a family of secreted proteins that elicit the profound effect of promoting survival of neurons in the developing mammalian nervous system. Although the role of neurotrophins in neuronal survival is firmly established, the mechanisms by which neurotrophins support survival of neurons remains to be elucidated. We propose to investigate the intracellular signaling mechanisms by which the neurotrophin brain-derived neurotrophic factor (BDNF) promotes the survival of granule neurons in the developing rat cerebellum. We have recently found that BDNF enhances the survival of cerebellar granule neurons via the extracellular regulated kinase (ERK) signaling pathway. The ERK activates kinases, the Rsks, cooperate with phosphotidylinositol-3 kinase (PI-3K)-Akt signaling pathway to directly inhibit the apoptotic protein BAD. In addition, preliminary data indicate that the transcription factor myocyte enhancer factor 2 (MEF2) previously implicated in myogenesis mediates BDNF-induced cerebellar granule cell survival. To elucidate the transcription-independent and transcription-dependent mechanisms by which BDNF-induced signal suppress the cell death machinery, we propose the following aims: (1) characterize the mechanisms that underlie the cooperativity of Rsk and Akt in suppressing the apoptotic protein BAD, (2) characterize the intracellular signal transduction pathway by which BDNF induced MEF-2 dependent transcription and neuronal survival, and (3) to determine the role that MEF2 plays in the survival of granule neurons in the intact cerebellar cortex in organotypic culture of the rat cerebellum. Together, the proposed experiments will provide critical insights into the intracellular signaling mechanism by which neurotrophin promote the survival of neurons in the mammalian CNS. Since neruotrophins can remarkably protect neurons against injury in the mature nervous system, our investigation should also provide valuable clues for the development of novel therapies aimed at alleviating neuronal cell death occurring in disorders of the nervous system including the devastating neurodegenerative diseases.